Abstract
Polyhydroxyalkanoates (PHAs) are a class of biopolyesters that are synthesized intracellularly by microorganisms, mainly by different genera of eubacteria. These biopolymers have diverse physical and chemical properties that also classify them as biodegradable in nature and make them compatible to living systems. In the last two decades or so, PHAs have emerged as potential useful materials in the medical field for different applications owing to their unique properties. The lower acidity and bioactivity of PHAs confer them with minimal risk compared to other biopolymers such as poly-lactic acid (PLA) and poly-glycolic acid (PGA). Therefore, the versatility of PHAs in terms of their non-toxic degradation products, biocompatibility, desired surface modifications, wide range of physical and chemical properties, cellular growth support, and attachment without carcinogenic effects have enabled their use as in vivo implants such as sutures, adhesion barriers, and valves to guide tissue repair and in regeneration devices such as cardiovascular patches, articular cartilage repair scaffolds, bone graft substitutes, and nerve guides. Here, we briefly describe some of the most recent innovative research involving the use of PHAs in medical applications. Microbial production of PHAs also provides the opportunity to develop PHAs with more unique monomer compositions economically through metabolic engineering approaches. At present, it is generally established that the PHA monomer composition and surface modifications influence cell responses.PHA synthesis by bacteria does not require the use of a catalyst (used in the synthesis of other polymers), which further promotes the biocompatibility of PHA-derived polymers.
Similar content being viewed by others
References
Bao G, Mitragotri S, Tong S (2013). Multifunctional nanoparticles for drug delivery and molecular imaging. Annu Rev Biomed Eng, 15: 253–282
Basnett P, Ching K Y, Stolz M, Knowles J C, Boccaccini A R, Smith C, Locke I C, Keshavarz T, Roy I (2013). Novel Poly (3-hydroxyoctanoate)/Poly (3-hydroxybutyrate) blends for medical applications. Reactive and Functional Polymers, 73(10): 1340–1348
Bennett R G (1988). Selection of wound closure materials. J Am Acad Dermatol, 18(4 Pt 1): 619–637
Borkenhagen M, Stoll R C, Neuenschwander P, Suter UW, Aebischer P (1998). In vivo performance of a new biodegradable polyester urethane system used as a nerve guidance channel. Biomaterials, 19(23): 2155–2165
Brigham C J, Sinskey A J (2012). Applications of polyhydroxyalkanoates in the medical industry. Int J Biotechnol Wellness Ind, 1: 52–60
Chen G Q, Wu Q (2005). The application of polyhydroxyalkanoates as tissue engineering materials. Biomaterials, 26(33): 6565–6578
Chen Q, Liang S, Thouas G A (2013). Elastomeric biomaterials for tissue engineering. Prog Polym Sci, 38(3-4): 584–671
Chen W, Tong Y W (2012). PHBV microspheres as neural tissue engineering scaffold support neuronal cell growth and axon-dendrite polarization. Acta Biomater, 8(2): 540–548
Chuah J A, Yamada M, Taguchi S, Sudesh K, Doi Y, Numata K (2013). Biosynthesis and characterization of polyhydroxyalkanoate containing 5-hydroxyvalerate units: Effects of 5HV units on biodegradability, cytotoxicity, mechanical and thermal properties. Polym Degrad Stabil, 98(1): 331–338
Dinjaski N, Fernández-Gutiérrez M, Selvam S, Parra-Ruiz F J, Lehman S M, San Román J, García E, García J L, García A J, Prieto M A (2014). PHACOS, a functionalized bacterial polyester with bactericidal activity against methicillin-resistant Staphylococcus aureus. Biomaterials, 35(1): 14–24
Doi Y, Kitamura S, Abe H (1995). Microbial synthesis and characterization of poly (3-hydroxybutyrate-co-3-hydroxyhexanoate). Macromolecules, 28(14): 4822–4828
Entholzner E, Mielke L, Pichlmeier R, Weber F, Schneck H (1995). [EEG changes during sedation with gamma-hydroxybutyric acid]. Anaesthesist, 44(5): 345–350
Freier T, Kunze C, Nischan C, Kramer S, Sternberg K, Sass M, Hopt U T, Schmitz K P (2002). In vitro and in vivo degradation studies for development of a biodegradable patch based on poly(3-hydroxybutyrate). Biomaterials, 23(13): 2649–2657
Gardel M, Schwarz U (2010). Cell-substrate interactions. J Phys Condens Matter, 22(19): 190301
Geiger B, Spatz J P, Bershadsky A D (2009). Environmental sensing through focal adhesions. Nat Rev Mol Cell Biol, 10(1): 21–33
Gogolewski S, Jovanovic M, Perren S M, Dillon J G, Hughes M K (1993). Tissue response and in vivo degradation of selected polyhydroxyacids: polylactides (PLA), poly(3-hydroxybutyrate) (PHB), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHB/VA). J Biomed Mater Res, 27(9): 1135–1148
Hazari A, Johansson-Ruden G, Junemo-Bostrom K, Ljungberg C, Terenghi G, Green C, Wiberg M (1999a) A new resorbable wraparound implant as an alternative nerve repair technique. Journal of Hand Surgery (British and European Volume) 24: 291–295
Hazari A, Wiberg M, Johansson-Rudén G, Green C, Terenghi G (1999b). A resorbable nerve conduit as an alternative to nerve autograft in nerve gap repair. Br J Plast Surg, 52(8): 653–657
He Y, Hu Z, Ren M, Ding C, Chen P, Gu Q, Wu Q (2013). Evaluation of PHBHHx and PHBV/PLA fibers used as medical sutures. J Mater Sci Mater Med, 25(2): 1–11
Hocking P, Marchessault R (1994). Biopolyesters Chemistry and Technology of BIODEGRADABLE POLymers. Blackie Academic & Professional, 48–96
Hon L Q, Ganeshan A, Thomas S M, Warakaulle D, Jagdish J, Uberoi R (2009). Vascular closure devices: a comparative overview. Curr Probl Diagn Radiol, 38(1): 33–43
Jones N, Cooper J, Waters R, Williams D (2000). Resorption profile and biological response of calcium phosphate filled PLLA and PHB7V. ASTM Spec Tech Publ, 1396: 69–82
Kai D, Loh X J (2014). Polyhydroxyalkanoates: Chemical modifications toward biomedical applications. ACS Sustain Chem& Eng, 2(2): 106–119
Kim H W, Chung C W, Rhee Y H (2005). UV-induced graft copolymerization of monoacrylate-poly(ethylene glycol) onto poly (3-hydroxyoctanoate) to reduce protein adsorption and platelet adhesion. Int J Biol Macromol, 35(1-2): 47–53
Köse G T, Korkusuz F, Korkusuz P, Purali N, Özkul A, Hasirci V (2003). Bone generation on PHBV matrices: an in vitro study. Biomaterials, 24(27): 4999–5007
Kostopoulos L, Karring T (1994). Guided bone regeneration in mandibular defects in rats using a bioresorbable polymer. Clin Oral Implants Res, 5(2): 66–74
Kunze C, Edgar Bernd H, Androsch R, Nischan C, Freier T, Kramer S, Kramp B, Schmitz K P (2006). In vitro and in vivo studies on blends of isotactic and atactic poly (3-hydroxybutyrate) for development of a dura substitute material. Biomaterials, 27(2): 192–201
Kuroda K, Caputo G A (2013). Antimicrobial polymers as synthetic mimics of host-defense peptides. Wiley Interdiscip Rev Nanomed Nanobiotechnol, 5(1): 49–66
Laycock B, Halley P, Pratt S, Werker A, Lant P (2013). The chemomechanical properties of microbial polyhydroxyalkanoates. Prog Polym Sci, 38(3-4): 536–583
Levine A C, Sparano A, Twigg FF, Numata K, Nomura C T (2015). Influence of cross-linking on the physical properties and cytotoxicity of polyhydroxyalkanoate (PHA) scaffolds for tissue engineering. ACS Biomater Sci Eng, 1(7): 567–576
Li J, Yun H, Gong Y, Zhao N, Zhang X (2005). Effects of surface modification of poly (3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) on physicochemical properties and on interactions with MC3T3-E1 cells. J Biomed Mater Res A, 75(4): 985–998
Li X, Chang H, Luo H, Wang Z, Zheng G, Lu X, He X, Chen F, Wang T, Liang J, Xu M (2015). Poly (3-hydroxybutyrate-co-3-hydroxyhexanoate) scaffolds coated with PhaP-RGD fusion protein promotes the proliferation and chondrogenic differentiation of human umbilical cord mesenchymal stem cells in vitro. J Biomed Mater Res A, 103(3): 1169–1175
Li X T, Sun J, Chen S, Chen G Q (2008). In vitro investigation of maleated poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) for its biocompatibility to mouse fibroblast L929 and human microvascular endothelial cells. J Biomed Mater Res A, 87(3): 832–842
Lizarraga-Valderrama L R, Nigmatullin R, Taylor C, Haycock J W, Claeyssens F, Knowles J C, Roy I (2015). Nerve tissue engineering using blends of poly (3-hydroxyalkanoates) for peripheral nerve regeneration. Eng Life Sci, 15(6): 612–621
Lomas A J, Webb W R, Han J, Chen G Q, Sun X, Zhang Z, El Haj A J, Forsyth N R (2013). Poly (3-hydroxybutyrate-co-3-hydroxyhexanoate)/ collagen hybrid scaffolds for tissue engineering applications. Tissue Eng Part C Methods, 19(8): 577–585
Lu H X, Yang Z Q, Jiao Q, Wang Y Y, Wang L, Yang P B, Chen X L, Zhang P B, Wang P, Chen M X, Lu X Y, Liu Y (2014). Low concentration of serum helps to maintain the characteristics of NSCs/NPCs on alkali-treated PHBHHx film in vitro. Neurol Res, 36(3): 207–214
Lu X, Wang L, Yang Z, Lu H (2013). Strategies of polyhydroxyalkanoates modification for the medical application in neural regeneration/ nerve tissue engineering. Adv Biosci Biotechnol, 4(06): 731–740
Luklinska Z B, Bonfield W (1997). Morphology and ultrastructure of the interface between hydroxyapatite-polyhydroxybutyrate composite implant and bone. J Mater Sci Mater Med, 8(6): 379–383
Mauclaire L, Brombacher E, Bünger J D, Zinn M (2010). Factors controlling bacterial attachment and biofilm formation on mediumchain- length polyhydroxyalkanoates (mcl-PHAs). Colloids Surf B Biointerfaces, 76(1): 104–111
McBeath R, Pirone D M, Nelson C M, Bhadriraju K, Chen C S (2004). Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell, 6(4): 483–495
Miller N D, Williams D F (1987). On the biodegradation of poly-betahydroxybutyrate (PHB) homopolymer and poly-beta-hydroxybutyrate- hydroxyvalerate copolymers. Biomaterials, 8(2): 129–137
Moy R L, Waldman B, Hein D W (1992). A review of sutures and suturing techniques. J Dermatol Surg Oncol, 18(9): 785–795
Mukai K, Doi Y, Sema Y, Tomita K (1993). Substrate specificities in hydrolysis of polyhydroxyalkanoates by microbial esterases. Biotechnol Lett, 15(6): 601–604
Naveen S V, Tan I K P, Goh Y S, Raghavendran H R B, Murali M R, Kamarul T (2015). Unmodified medium chain length polyhydroxyalkanoate (uMCL-PHA) as a thin film for tissue engineering application–characterization and in vitro biocompatibility. Mater Lett, 141: 55–58
Nelson T, Kaufman E, Kline J, Sokoloff L (1981). The extraneural distribution of g-hydroxybutyrate. J Neurochem, 37(5): 1345–1348
Novikov L N, Novikova L N, Mosahebi A, Wiberg M, Terenghi G, Kellerth J O (2002). A novel biodegradable implant for neuronal rescue and regeneration after spinal cord injury. Biomaterials, 23(16): 3369–3376
Novikova L N, Pettersson J, Brohlin M, Wiberg M, Novikov L N (2008). Biodegradable poly-beta-hydroxybutyrate scaffold seeded with Schwann cells to promote spinal cord repair. Biomaterials, 29(9): 1198–1206
O’Connor S, Szwej E, Nikodinovic-Runic J, O’Connor A, Byrne A T, Devocelle M, O’Donovan N, Gallagher W M, Babu R, Kenny S T, Zinn M, Zulian Q R, O’Connor K E (2013). The anti-cancer activity of a cationic anti-microbial peptide derived from monomers of polyhydroxyalkanoate. Biomaterials, 34(11): 2710–2718
Pawan G L, Semple S J (1983). Effect of 3-hydroxybutyrate in obese subjects on very-low-energy diets and during therapeutic starvation. Lancet, 1(8314-5): 15–17
Pelham R J, Wang Y (1997). Cell locomotion and focal adhesions are regulated by substrate flexibility. Proc Natl Acad Sci USA, 94(25): 13661–13665
Peng SW, Guo X Y, Shang G G, Li J, Xu X Y, You ML, Li P, Chen G Q (2011). An assessment of the risks of carcinogenicity associated with polyhydroxyalkanoates through an analysis of DNA aneuploid and telomerase activity. Biomaterials, 32(10): 2546–2555
Philip S, Keshavarz T, Roy I (2007). Polyhydroxyalkanoates: biodegradable polymers with a range of applications. J Chem Technol Biotechnol, 82(3): 233–247
Qu X H, Wu Q, Liang J, Qu X, Wang S G, Chen G Q (2005). Enhanced vascular-related cellular affinity on surface modified copolyesters of 3-hydroxybutyrate and 3-hydroxyhexanoate (PHBHHx). Biomaterials, 26(34): 6991–7001
Qu X H, Wu Q, Zhang K Y, Chen G Q (2006). In vivo studies of poly(3- hydroxybutyrate-co-3-hydroxyhexanoate) based polymers: biodegradation and tissue reactions. Biomaterials, 27(19): 3540–3548
Ricotti L, Polini A, Genchi G G, Ciofani G, Iandolo D, Vazão H, Mattoli V, Ferreira L, Menciassi A, Pisignano D (2012). Proliferation and skeletal myotube formation capability of C2C12 and H9c2 cells on isotropic and anisotropic electrospun nanofibrous PHB scaffolds. Biomed Mater, 7(3): 035010
Saito T, Tomita K, Juni K, Ooba K (1991). In vivo and in vitro degradation of poly(3-hydroxybutyrate) in rat. Biomaterials, 12(3): 309–312
Shangguan Y Y, Wang Y W, Wu Q, Chen G Q (2006). The mechanical properties and in vitro biodegradation and biocompatibility of UVtreated poly(3-hydroxybutyrate-co-3-hydroxyhexanoate). Biomaterials, 27(11): 2349–2357
Shen F, Zhang E, Wei Z (2009). Surface bio-modification of poly (hydroxybutyrate-co-hydroxyhexanoate) and its aging effect. Colloids Surf B Biointerfaces, 73(2): 302–307
Shishatskaya E I, Volova T G, Gordeev S A, Puzyr A P (2005). Degradation of P(3HB) and P(3HB-co-3HV) in biological media. J Biomater Sci Polym Ed, 16(5): 643–657
Shrivastav A, Kim H Y, Kim Y R (2013). Advances in the applications of polyhydroxyalkanoate nanoparticles for novel drug delivery system. BioMed Res Int, 2013: 581684
Sodian R, Hoerstrup S P, Sperling J S, Daebritz S, Martin D P, Moran A M, Kim B S, Schoen F J, Vacanti J P, Mayer J E (2000). Early in vivo experience with tissue-engineered trileaflet heart valves. Circulation, 102(19 Suppl 3): III22–III29
Stock U A, Degenkolbe I, Attmann T, Schenke-Layland K, Freitag S, Lutter G (2006). Prevention of device-related tissue damage during percutaneous deployment of tissue-engineered heart valves. J Thorac Cardiovasc Surg, 131(6): 1323–1330
Sun J, Dai Z, Zhao Y, Chen G-Q (2007). In vitro effect of oligohydroxyalkanoates on the growth of mouse fibroblast cell line L929. Biomaterials, 28: 3896–3903
Taylor M S, Daniels A U, Andriano K P, Heller J (1994). Six bioabsorbable polymers: in vitro acute toxicity of accumulated degradation products. J Appl Biomater, 5(2): 151–157
Tezcaner A, Bugra K, Hasirci V (2003). Retinal pigment epithelium cell culture on surface modified poly(hydroxybutyrate-co-hydroxyvalerate) thin films. Biomaterials, 24(25): 4573–4583
Valappil S P, Misra S K, Boccaccini A R, Roy I (2006). Biomedical applications of polyhydroxyalkanoates: an overview of animal testing and in vivo responses. Expert Rev Med Devices, 3(6): 853–868
Volova T, Goncharov D, Sukovatyi A, Shabanov A, Nikolaeva E, Shishatskaya E (2013). Electrospinning of polyhydroxyalkanoate fibrous scaffolds: effects on electrospinning parameters on structure and properties. J Biomater Sci Polym Ed, 25(4): 370–393
Wang Y, Jiang X L, Peng S W, Guo X Y, Shang G G, Chen J C, Wu Q, Chen G Q (2013). Induced apoptosis of osteoblasts proliferating on polyhydroxyalkanoates. Biomaterials, 34(15): 3737–3746
Wang Y, Jiang X L, Yang S C, Lin X, He Y, Yan C, Wu L, Chen G Q, Wang Z Y, Wu Q (2011). MicroRNAs in the regulation of interfacial behaviors of MSCs cultured on microgrooved surface pattern. Biomaterials, 32(35): 9207–9217
Wang Y W, Wu Q, Chen G Q (2004). Attachment, proliferation and differentiation of osteoblasts on random biopolyester poly(3-hydro-xybutyrate-co-3-hydroxyhexanoate) scaffolds. Biomaterials, 25(4): 669–675
Wang Y W, Wu Q, Chen G Q (2005). Gelatin blending improves the performance of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) films for biomedical application. Biomacromolecules, 6(2): 566–571
Wei X, Hu Y J, Xie WP, Lin R L, Chen G Q (2009). Influence of poly(3- hydroxybutyrate-co-4-hydroxybutyrate-co-3-hydroxyhexanoate) on growth and osteogenic differentiation of human bone marrowderived mesenchymal stem cells. J Biomed Mater Res A, 90(3): 894–905
Wu Q, Wang Y, Chen G Q (2009). Medical application of microbial biopolyesters polyhydroxyalkanoates Artificial Cells. Blood Substitutes and Biotechnology, 37(1): 1–12
Xu X Y, Li X T, Peng SW, Xiao J F, Liu C, Fang G, Chen K C, Chen G Q (2010). The behaviour of neural stem cells on polyhydroxyalkanoate nanofiber scaffolds. Biomaterials, 31(14): 3967–3975
Yan C, Wang Y, Shen X Y, Yang G, Jian J, Wang H S, Chen G Q, Wu Q (2011). MicroRNA regulation associated chondrogenesis of mouse MSCs grown on polyhydroxyalkanoates. Biomaterials, 32(27): 6435–6444
Yang X, Zhao K, Chen G Q (2002). Effect of surface treatment on the biocompatibility of microbial polyhydroxyalkanoates. Biomaterials, 23(5): 1391–1397
Yu B Y, Chen C R, Sun Y M, Young T H (2009). The response of rat cerebellar granule neurons (rCGNs) to various polyhydroxyalkanoate (PHA) films. Desalination, 245(1-3): 639–646
Zhao K, Deng Y, Chun Chen J, Chen G Q (2003). Polyhydroxyalkanoate (PHA) scaffolds with good mechanical properties and biocompatibility. Biomaterials, 24(6): 1041–1045
Zhao K, Yang X, Chen G Q, Chen J C (2002). Effect of lipase treatment on the biocompatibility of microbial polyhydroxyalkanoates. J Mater Sci Mater Med, 13(9): 849–854
Zhao Q, Wang S, Kong M, Geng W, Li R K, Song C, Kong D (2012). Phase morphology, physical properties, and biodegradation behavior of novel PLA/PHBHHx blends. J Biomed Mater Res B Appl Biomater, 100(1): 23–31
Zink D, Fischer A H, Nickerson J A (2004). Nuclear structure in cancer cells. Nat Rev Cancer, 4(9): 677–687
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ali, I., Jamil, N. Polyhydroxyalkanoates: Current applications in the medical field. Front. Biol. 11, 19–27 (2016). https://doi.org/10.1007/s11515-016-1389-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11515-016-1389-z